Sodium Restriction Counseling Reduces Cardiac Events in Patients With Heart Failure.

BACKGROUND: Many heart failure (HF) guidelines recommend sodium restriction for patients with HF, but the outcome of sodium restriction counseling (SRC) for HF patients is still unknown. We wanted to clarify whether SRC reduces cardiac events in patients with HF.Methods and Results:Overall, 800 patients (77±12 years) who were hospitalized for HF were enrolled. During HF hospitalization, patients received SRC; patients were required to have a salt intake of <6 g/day. After discharge, death or HF rehospitalization events were investigated. During a mean follow-up of 319±252 days, 83 patients died, and 153 patients were rehospitalized for HF. SRC significantly decreased all-cause death (odds ratio, 0.42; 95% confidence interval [CI], 0.23-0.76; P<0.01), especially cardiac death of hospitalized HF patients after discharge. In the multivariate analysis adjusted for age, sex, SRC, body mass index, hypertension, dyslipidemia, ß-blockers, and mineralocorticoid receptor antagonist intake, cardiac rehabilitation, and the type of HF, SRC remained a significant predictor of death. Kaplan-Meier analysis showed that SRC significantly reduced deaths and the combined outcome of HF rehospitalization and death. In patients with reduced left ventricular ejection fraction, SRC significantly decreased the mortality rate (odds ratio, 0.27; 95% CI, 0.10-0.71; P<0.01). CONCLUSIONS: SRC reduced the mortality rate after discharge of hospitalized HF patients.

Differential regulation of airway smooth muscle cell migration by E-prostanoid receptor subtypes.

Migration of airway smooth muscle (ASM) cells plays an important role in the pathophysiology of airway hyperresponsiveness and remodeling in asthma. It has been reported that prostaglandin (PG)E2 inhibits migration of ASM cells. Although PGE2 regulates cellular functions via binding to distinct prostanoid EP receptors, the role of EP receptor subtypes in mechanisms underlying cell migration has not been fully elucidated. We investigated the role of EP receptors in the inhibitory effects of PGE2 on the migration of human ASM cells. Migration induced by platelet-derived growth factor (PDGF)-BB (10 ng/ml, 6 h) was assessed by a chemotaxis chamber assay. PDGF-BB-induced cell migration was inhibited by PGE2, the specific EP2 agonist ONO-AE1-259-01, the specific EP4 agonist ONO-AE1-329, and cAMP-mobilizing agents. The inhibition of cell migration by PGE2 was significantly reversed by a blockade of EP2 and EP4 receptors using antagonists or transfection with siRNAs. Moreover, PGE2, the EP2 agonist, and the EP4 agonist significantly increased phosphorylation of small heat shock protein 20, one of the protein substrates for protein kinase A (PKA), with depolymerization of actin. In contrast, the EP3 agonist ONO-AE-248 significantly promoted baseline cell migration without affecting PDGF-BB-induced cell migration. In summary, activation of EP2 and EP4 receptors and subsequent activation of the cAMP/PKA pathway are the main mechanisms of inhibition of ASM cell migration by PGE2. HSP20 phosphorylation by PKA is possibly involved in this mechanism. Conversely, EP3 is potent in promoting cell migration. EP receptor subtypes may be novel therapeutic target molecules in airway remodeling and asthma.

Melinjo (Gnetum gnemon L.) Seed Extract Decreases Serum Uric Acid Levels in Nonobese Japanese Males: A Randomized Controlled Study.

Melinjo (Gnetum gnemon L.) seed extract (MSE) containing trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene) and other derivatives exerts various beneficial effects. However, its mechanism of action in humans remains unknown. In this study, we aimed to investigate beneficial effects of MSE in healthy adult males. In this double-blind, randomized controlled study, 30 males aged 35-70 years with ≤10% flow-mediated dilatation received placebo or 750 mg MSE powder for 8 weeks, and twenty-nine males (45.1 ± 8.8 years old) completed the trial. There was a significant difference in the melinjo and placebo groups. Compared with the placebo control, MSE significantly reduced serum uric acid at 4 weeks and 8 weeks (n = 14 and 15, resp.). HDL cholesterol was significantly increased in the melinjo group. To clarify the mechanism of MSE for reducing uric acid, we investigated xanthine oxidase inhibitory activity, angiotensin II type 1 (AT1) receptor binding inhibition rate, and agonistic activities for PPAR α and PPAR γ . MSE, trans-resveratrol, and a resveratrol dimer, gnetin C (GC), significantly inhibit AT1 receptor binding and exhibit mild agonistic activities for PPAR α and PPAR γ . In conclusion, MSE may decrease serum uric acid regardless of insulin resistance and may improve lipid metabolism by increasing HDL cholesterol.

Prostaglandin E2 enhances interleukin-8 production via EP4 receptor in human pulmonary microvascular endothelial cells.

Prostaglandin E(2) (PGE(2)) is a bioactive prostanoid implicated in the inflammatory processes of acute lung injury/acute respiratory distress syndrome. This study investigated whether PGE(2) can induce production of interleukin (IL)-8, the major chemokine for neutrophil activation, from human pulmonary microvascular endothelial cells (HPMVECs). PGE(2) significantly enhanced IL-8 protein production with increases in IL-8 mRNA expression and intracellular cAMP levels. HPMVECs expressed only EP4 receptor mRNA. The PGE(2) effects were mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and inhibited by a selective EP4 receptor antagonist, ONO-AE3-208, or a protein kinase A inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt. The specific agonist for EP1, EP2, or EP3 receptor did not induce IL-8 production. PGE(2)-induced IL-8 production was accompanied by p38 phosphorylation and was significantly inhibited by a p38 inhibitor, SB-203580, but not by an ERK1/2 inhibitor, U-0126, or a JNK inhibitor, SP-600125. Additionally, PGE(2) increased cyclooxygenase-2 expression with no change in constitutive cyclooxygenase-1 expression, suggesting possible involvement of an autocrine or paracrine manner. In conclusion, PGE(2) enhances IL-8 production via EP4 receptor coupled to G(s) protein in HPMVECs. Activation of the cAMP/protein kinase A pathway, followed by p38 activation, is essential for these mechanisms. Because neutrophils play a critical role in the inflammation of acute lung injury/acute respiratory distress syndrome, IL-8 released from the pulmonary microvasculature in response to PGE(2) may contribute to pathophysiology of this disease.

Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca(2+) concentrations in human airway smooth muscle cells.

Increased airway smooth muscle mass due to cell proliferation contributes to airway hyper-responsiveness and remodeling in patients with asthma. Prostaglandin E2 (PGE2) inhibits proliferation of airway smooth muscle cells, but the role of prostanoid EP receptor subtypes in mechanisms involved has not been fully elucidated yet. We investigated the effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca(2+) concentrations ([Ca(2+)]i) in human airway smooth muscle cells. Cell numbers were assessed by mitochondria-dependent reduction of 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate to formazan (WST-1 assay). RT-PCR data showed that human airway smooth muscle cells express EP2, EP3, and EP4 but not EP1 receptor mRNA. PGE2 (1nM-1µM) inhibited cell proliferation induced by 5% fetal bovine serum (FBS) in a concentration-dependent manner. (16S)-9-deoxy-9ß-chloro-15-deoxy-16-hydroxy-17, 17-trimethylene-19, 20-didehydro PGE2 sodium salt (ONO-AE1-259-01; EP2 receptor agonist) and 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia PGE2 (ONO-AE1-329; EP4 receptor agonist) inhibited the 5% FBS-induced cell proliferation. ONO-AE1-259-01 and ONO-AE1-329 also significantly increased the cytosolic cAMP levels. In contrast, 11,15-O-dimethyl PGE2 (ONO-AE-248; EP3 receptor agonist) elicited an oscillatory increase in [Ca(2+)]i but did not affect the cell growth or cAMP levels. [(17S)-2,5-ethano-6-oxo-17,20-dimethyl PGE1] (ONO-DI-004; EP1 receptor agonist) did not affect cell growth, cAMP levels, or [Ca(2+)]i. In conclusion, PGE2 inhibits FBS-induced cell proliferation mostly via EP2 and EP4 receptor activation and subsequent cAMP elevation. The EP3 receptor agonist causes an increase in [Ca(2+)]i without affecting cell growth. There is no functional expression of the EP1 receptor. Research on prostanoid EP receptors may lead to novel therapeutic strategies for treatment of asthma.

Syntheses, structural characterization and photophysical properties of 4-(2-pyridyl)-1,2,3-triazole rhenium(I) complexes.

Novel chelators, i.e., 4-(2-pyridyl)-1,2,3-triazole derivatives, were synthesized by means of Cu(I)-catalyzed 1,3-dipolar cycloaddition and used to prepare luminescent Re(I) complexes [ReCl(CO)(3)(Bn-pyta)], [ReCl(CO)(3)(AcGlc-pyta)] and [ReCl(CO)(3)(Glc-pyta)] (Bn-pyta = 1-benzyl-4-(2-pyridyl)-1,2,3-triazole, AcGlc-pyta = 2-(4-(2-pyridyl)-1,2,3-triazol-1-yl)ethyl 2,3,4,6-tetra-O-acetyl-beta-d-glucopyranoside, Glc-pyta = 2-(4-(2-pyridyl)-1,2,3-triazol-1-yl)ethyl beta-d-glucopyranoside). X-Ray crystallography of Bn-pyta and Glc-pyta indicated an azocompound-like structure while the 1,2,4-triazole isomer has an azine character. [ReCl(CO)(3)(Bn-pyta)] crystallized in the monoclinic system with space group P2(1)/n. Bn-pyta ligand coordinates with the nitrogen atoms of the 2-pyridyl group and the 3-position of 1,2,3-triazole ring, which is a very similar coordinating fashion to that of the 2,2'-bipyridine derivative. The glucoconjugated Re(I) complexes [ReCl(CO)(3)(AcGlc-pyta)] and [ReCl(CO)(3)(Glc-pyta)] hardly crystallized, and were analyzed by applying extended X-ray absorption fine structure (EXAFS) analysis. The EXAFS analyses suggested that the glucoconjugation at the 1-position of the 1,2,3-triazole makes no influence to the coordinating fashion of 4-(2-pyridyl)-1,2,3-triazole. [ReCl(CO)(3)(Bn-pyta)] showed a blue-shifted maximum absorption (333 nm, 3.97 x 10(3) M(-1) cm(-1)) compared with [ReCl(CO)(3)(bpy)] (371 nm, 3.35 x 10(3) M(-1) cm(-1)). These absorptions were clearly assigned to be the mixed metal-ligand-to-ligand charge transfer (MLLCT) on the basis of time-dependent density functional theory calculation. The luminescence spectrum of [ReCl(CO)(3)(Bn-pyta)] also showed this blue-shifted feature when compared with that of [ReCl(CO)(3)(bpy)]. The luminescence lifetime of [ReCl(CO)(3)(Bn-pyta)] was determined to be 8.90 mus in 2-methyltetrahydrofuran at 77 K, which is longer than that of [ReCl(CO)(3)(bpy)] (3.17 micros). The blue-shifted electronic absorption and elongated luminescence lifetime of [ReCl(CO)(3)(Bn-pyta)] suggested that 4-(2-pyridyl)-1,2,3-triazole functions as an electron-rich bidentate chelator.